Devices and methods of treating methamphetamine addiction and medical and behavioral consequences of methamphetamine use and of hiv infection

ABSTRACT

A method of treating a condition of in a human patient comprising pharmacologically activating a translocator protein of 18 kDa (TSPO), wherein the condition is one of a chronic methamphetamine addiction, a medical consequence of methamphetamine use; a behavioral consequence of methamphetamine use, an HIV associated cognitive motor disorder, an HIV-associated neurodegenerative disorder, and a neuroinflammatory response.

CROSS REFERENCE TO RELATED APPLICATIONS/PRIORITY

The present invention claims priority to U.S. Provisional PatentApplication No. 62/182,054 filed Jun. 19, 2015, U.S. Provisional PatentApplication No. 62/190,287 filed Jul. 9, 2015, and U.S. patentapplication Ser. No. 15/175,284 filed Jun. 7, 2016, which are allincorporated by reference into the present disclosure as if fullyrestated herein. To the extent that there is any conflict between theincorporated material and the present disclosure, the present disclosurewill control.

FIELD OF THE INVENTION

The present invention relates to a methods and devices for treatingmethamphetamine addiction and medical and behavioral consequences ofmethamphetamine use and HIV infection.

BACKGROUND OF THE INVENTION

Methamphetamine abuse and related problems: Methamphetamine (MA) is ahighly addictive psychomotor stimulant that is a unique drug of abusefor several reasons, not the least of which includes its userpopulation. There has been a dramatic increase in methamphetamine use inthe United States over the past 25 years, especially among women. Arecent survey by the Substance Abuse and Mental Health ServicesAdministration showed that males are more likely to use marijuana,cocaine and hallucinogens, while men and women use methamphetamine atequal rates. In addition women tend to initiate methamphetamine useearlier than men and prefer to use methamphetamine over other addictivedrugs. The use of methamphetamine has been linked to cognitive defect,violence, risk-taking behaviors and criminal activity, even among femaleusers. For example, women methamphetamine users are considered to besignificantly more violent than men. While high on methamphetamine, bothmale and female methamphetamine users also report engaging in riskysexual behaviors (e.g., unprotected, with strangers, with multiplepartners at once), decreased sexual inhibition, heightened sexual desireand arousal, and enhanced sexual pleasure, and they engage in prolongedsexual contact. These risky sexual behaviors contribute to the spread ofHIV/AIDS, which has been a major public health concern for severaldecades.

Another particularly unique characteristic of methamphetamine use is theway in which the drug is self-administered by humans, which is typicallyin a “binge and crash” manner. While a clear definition of the binge useof methamphetamine is lacking in current scientific literature,according to self-reports by methamphetamine users, a binge can bedescribed as taking methamphetamine for a long period of time “until yourun out [of the drug] or just can't physically do it anymore”. Amethamphetamine binge in humans can range from 3-22 days. Furthermore,it has been reported that a history of unrestricted access tomethamphetamine leads to increases in methamphetamine taking in bothhumans and animals.

Cognitive deficits (memory problems, decreased cognitive flexibility)—Data from both humans and animals show that chronic methamphetamine usecan lead to disruptions of brain functioning that can affect bothbehavioral and neurochemical functioning, including deleterious effectson memory and cognition. Additionally, chronic methamphetamine use hasbeen established as a risk factor for neuropsychological impairment.Approximately 40% of individuals who chronically use methamphetamineexhibit neurocognitive impairments, resulting in problems with executivefunctioning and psychomotor skill functioning. Even more striking, morethan two-thirds of methamphetamine-dependent users exhibit impairment inoverall learning, free recall and repetitions. Of particular importanceare the effects of methamphetamine on episodic memory. Episodic memoryis unique since it is the memory of learning a particular event, as wellas what was learned during the event. Nearly 50% ofmethamphetamine-dependent individuals demonstrate impaired episodicmemory, making it the most common type of memory affected inmethamphetamine users. This impairment in episodic memory ischaracterized by a limited use of higher-level encoding, decreases incognitive flexibility and increases in perseverance. Brain regionsinvolved in cognitive function and memory include the prefrontal cortex,hippocampus, striatum and amygdala. Although the precise mechanisms bywhich methamphetamine disrupts episodic memory are unknown, it isgenerally believed that these cognitive disruptions are due to theneurotoxic effects of methamphetamine on dopaminergic, serotonergic andnoradrenergic neurons in these brain regions. For example, human andanimal studies have shown that depletion of dopamine (DA) in thestriatum can lead to deficits in overall reaction task performance.Additionally, disruptions in serotonin (5-HT) and dopamine signalinghave been shown to increase impulsivity, while depletion of centralserotonin can disrupt the ability to accurately detect and respond tovisual stimuli, all of which impair the ability of a subject to completea learning or memory task.

Aberrant sexual behavior (sexual deviance, risky sexual behavior, HIVtransmission)—With continued use of methamphetamine, especially when theuser progresses to intravenous administration, the drug becomesprimarily associated with sexual activity. The association betweenmethamphetamine use and sexual risk taking has been well documented inmen and predominantly among men who have sex with men. Studies haveshown that methamphetamine use in men has been associated with high-risksexual behaviors such as having a higher number of sexual partners,infrequent condom use, trading drugs or money for sex, having sex with apartner who is an injection drug user, as well as reports of a recentsexually transmitted infection (STI). While fewer studies have beenconducted to examine the relationship between methamphetamine use andthe risk of STIs among women, there are data suggesting that theproportion of methamphetamine use by either sex is more similar thanwith other illicit substances. Interestingly, current literature reviewssuggest higher rates of bacterial STIs reported in female as comparedwith male drug users. Women may be more susceptible to STIs owing to theincreased likelihood of asymptomatic infection and the practice ofexchanging sex for money or drugs. One study of injection drug usersfound that methamphetamine-injecting women were more likely to haveunprotected vaginal sex and multiple sex partners compared to women whoinjected other substances. A recent review of sexual behaviors amongheterosexual drug users indicated that women methamphetamine users wereat increased risk for engaging in unsafe sexual behaviors. Other studieshave documented that women experience a heightened sex drive andincreased number of sexual acts under the influence of methamphetamine.Qualitative data also suggest that methamphetamine use increases sexualdesire and pleasure and reduces inhibition, which can alter/increasesexual behaviors in women. Recent preclinical research in rodent modelsof drug-induced sexual motivation also revealed a critical role forprogesterone signaling in the medial amygdala on methamphetamine-relatedsexual behaviors in female rats. However, despite existing evidence,there is an urgent need for further research on sexual-risk behavioramong women who use methamphetamine because of their potentially highrisk for STIs and HIV.

There is currently not a treatment available that reducesmethamphetamine cravings and medical and behavioral consequences ofmethamphetamine use or the HIV associated cognitive motor disorders andHIV-associated neurodegenerative disorders.

SUMMARY OF THE INVENTION

Wherefore, it is an object of the present invention to overcome theabove mentioned shortcomings and drawbacks associated with the priorart.

The neurotoxic effects of HIV-1 are primarily attributed to its abilityto readily penetrate into the central nervous system (CNS) early duringthe course of infection. Deficiency in the functionality of dopaminergicneurons has been observed to be associated with early stage HIV-1infection. Interestingly, long-term methamphetamine use is alsoassociated with the loss of dopaminergic neurons and functionality.Although the introduction of highly active antiretroviral therapy(HAART) has significantly reduced the incidence of HIV-associateddementia, milder neurotoxicity, including minor cognitive motordisorders and HIV-associated neurodegenerative disorders have increasedin incidence. In addition, many anti-retroviral drugs fail to penetratethe blood brain barrier, thus making it difficult to treat thesepatients. HIV-associated neurotoxicity is primarily thought to bemediated by the neurotoxins released from infected cells, primarilyresident microglia, after migration of the infected cells through theblood brain barrier. The frontostriatal regions of the brain are highlyvulnerable to this so-called “Trojan Horse” mechanism by which HIV-1penetrates the central nervous system. Methamphetamine also targetsthese frontostriatal regions by increasing dopaminergic andglutamatergic neurotransmission, which leads to further neuronal damageand cell death. Multiple models for methamphetamine-mediatedneurotoxicity have been proposed, including a role for cross-talkbetween neuroinflammation induced by methamphetamine and HIV throughreactive gliosis. Interestingly, activation of the translocator proteinof 18 kDa (TSPO) may mediate a functional antiviral mechanism viaprotein misfolding during HIV glycoprotein synthesis.

As discussed more fully below, chronic methamphetamine administrationresults in a neuroinflammatory response characterized by a markedincrease in TSPO receptor binding and microglial activation. Thisneuroinflammatory response is remarkably similar to effects demonstratedin patients with HIV-associated cognitive problems. Enhanced TSPObinding is seen in ˜25% of HIV-positive patients, a subset who alsoexhibit a cluster of cognitive and executive deficits known asHIV-associated dementia. This increased TSPO binding in cortical regionsis correlated to other markers of microglial activation and synapticdisruption. Even HIV-infected patients on long-term antiretroviraltherapy (ART; i.e., those without viral load) show focal areas ofenhanced TSPO binding in the corpus callosum, cingulate gyrus andtemporal and frontal cortices. This pattern is supported by nonhumanprimate research, demonstrating a similar increase in TSPO binding andneuroinflammation in simian immunodeficiency virus (SIV)-relatedencephalitis.

Another object of the present invention is to pharmacologically activatethe translocator protein of 18 kDa (TSPO) to clinically treat cognitiveand behavior consequences of methamphetamine addiction, especiallychronic methamphetamine addiction, and the HIV associated cognitivemotor disorders and HIV-associated neurodegenerative disorders. The TSPOagonists include Ro5-4864, other peripheral benzodiazepines orderivatives, and new compounds developed as agonists for the TSPO,especially those which have relatively low or no binding affinity forthe gamma-aminobutyric acid A (GABA_(A)) receptor.

A further object of the present invention is to provide pharmacologicaltherapies to treat specific medical consequences associated withmethamphetamine addiction as well as the methamphetamine dependenceitself.

The present invention also relates to a method of treating chronicmethamphetamine addiction in a human patient comprising the step ofadministering to the patient a therapeutically effective amount of abenzodiazepine with a halogen moiety in the 4′ position.

The present invention also relates to a method of treating one of HIVassociated cognitive motor disorders and HIV-associatedneurodegenerative disorders in a human comprising the step ofpharmacologically activating the translocator protein of 18 kDa (TSPO).

The present invention also relates to a method of treatingneuroinflammatory response in a human comprising the step ofpharmacologically activating the translocator protein of 18 kDa (TSPO).

One aspect of the present invention relates to methods of treating acondition of in a human patient comprising pharmacologically activatinga translocator protein of 18 kDa (TSPO), wherein the condition is one ofa chronic methamphetamine addiction, a medical consequence ofmethamphetamine use, a behavioral consequence of methamphetamine use, anHIV associated cognitive motor disorder, an HIV-associatedneurodegenerative disorder, and a neuroinflammatory response. In anadditional embodiment the medical consequence is cognitive defect. In anadditional embodiment the behavioral consequence is one of increasedviolence, risk-taking behaviors, propensity for criminal activity, andaberrant sexual behavior. In an additional embodiment the human is afemale. An additional embodiment includes the step of pharmacologicallyactivating the translator protein of 18 kDa (TSPO) by administering atherapeutically effective amount of a benzodiazepine that preferentiallytargets TSPO over a GABAA receptor. An additional embodiment includesthe step of pharmacologically activating the translator protein of 18kDa (TSPO) by administering a therapeutically effective amount of abenzodiazepine that has a halogen bound to a 4′ carbon in thebenzodiazepine. In an additional embodiment the translator protein of 18kDa (TSPO) is pharmacologically activated by administering atherapeutically effective amount of one or more peripheralbenzodiazepine receptor ligands selected from a group consisting of:Ro5-5115, Ro5-5119, Ro5-5120, Ro5-5122, Ro5-5888, Ro5-4864, Ro5-6524,Ro5-6528, Ro5-6531, Ro5-6900, Ro5-6902, Ro5-6945, and Ro5-6993, oxazepamand therapeutically acceptable salt, solvate, clathrate, stereoisomer,enantiomer or prodrug of these compounds or mixtures thereof. Anadditional embodiment includes the step of administering atherapeutically effective amount of one or more of an agonist(activator) of potassium-chloride co-transporter 2 (KCC2) and aninhibitor (antagonist) of 20 alpha-hydroxysteroid dehydrogenase (20alpha-HSD) and therapeutically acceptable salt, solvate, clathrate,stereoisomer, enantiomer or prodrug of these compounds or mixturesthereof.

A further aspect of the present invention includes therapeutic productscomprising a first component being a benzodiazepine with a halogenmoiety in a 4′ position or a therapeutically acceptable salt, solvate,clathrate, stereoisomer, enantiomer or prodrug of thereof, and a secondcomponent being one of an agonist (activator) of potassium-chlorideco-transporter 2 (KCC2) and/or an inhibitor (antagonist) of20alpha-hydroxysteroid dehydrogenase (20 alpha-HSD) or a therapeuticallyacceptable salt, solvate, clathrate, stereoisomer, enantiomer or prodrugof these compound or mixtures thereof. In an additional embodiment thefirst component is selected from a group consisting of: Ro5-5115,Ro5-5119, Ro5-5120, Ro5-5122, Ro5-5888, Ro5-4864, Ro5-6524, Ro5-6528,Ro5-6531, Ro5-6900, Ro5-6902, Ro5-6945, and Ro5-6993, oxazepam andtherapeutically acceptable salt, solvate, clathrate, stereoisomer,enantiomer or prodrug of these compounds or mixtures thereof.

In another aspect, the present invention features a methods and devicesfor treating methamphetamine addiction and medical and behavioralconsequences of methamphetamine use and HIV infection, where the methodincludes the administration of a pharmaceutical composition of aneffective amount of an activator of translator protein of 18 kDa(activator of TSPO), or a pharmaceutically acceptable salt, solvate,clathrate, stereoisomer, enantiomer or prodrug thereof.

In some embodiments, the activator of TSPO, or a pharmaceuticallyacceptable salt, solvate, or clathrate, stereoisomer, enantiomer orprodrug thereof, is administered as a pharmaceutical composition thatfurther includes a pharmaceutically acceptable excipient.

In some embodiments, the activator of TSPO is a compound with the basicbenzodiazepine structure, but with a halogen moiety (e.g., chlorine,fluorine, bromine, iodine) in the 4′ position.

In some embodiments, the mammal is a human.

In other embodiments, the activator of TSPO is administered at a dosethat is between. 0.05 mg-5 mg/kg weight of the human.

In certain embodiments, the pharmaceutical composition is formulated fororal administration.

In other embodiments, the pharmaceutical composition is formulated forextended release.

In still other embodiments, the pharmaceutical composition is formulatedfor immediate release.

In some embodiments, the pharmaceutical composition is administeredconcurrently with one or more therapeutic agents for the treatingmethamphetamine addiction and/or medical and/or behavioral consequencesof methamphetamine use and/or HIV infection.

In some embodiments, the activator of TSPO, or a pharmaceuticallyacceptable salt, solvate, clathrate, stereoisomer, enantiomer or prodrugthereof, is administered as a pharmaceutical composition that furtherincludes a pharmaceutically acceptable excipient.

In some embodiments, administration of the pharmaceutical composition toa human results in a peak plasma concentration of the activator of TSPObetween 0.05 μM-10 μM (e.g., between 0.05 μM-5 μM).

In some embodiments, the mammal is a human, preferably a female human.

In other embodiments, the activator of TSPO is administered at a dosethat is between 0.05 mg-5 mg/kg weight of the human.

In certain embodiments, the pharmaceutical composition is formulated fororal administration.

In other embodiments, the pharmaceutical composition is formulated forextended release.

In still other embodiments, the pharmaceutical composition is formulatedfor immediate release.

In some embodiments, the pharmaceutical composition is administeredconcurrently with one or more therapeutic agents for the treatment orprevention of neuroinflammation.

As used herein, the term “delayed release” refers to a pharmaceuticalpreparation, e.g., an orally administered formulation, which passesthrough the stomach substantially intact and dissolves in the smalland/or large intestine (e.g., the colon). In some embodiments, delayedrelease of the active agent (e.g., one of the TSPO compounds asdescribed herein) results from the use of an enteric coating of an oralmedication (e.g., an oral dosage form). The active agent may also bereferred to as the active compound, active ingredient, active material,and/or the active drug substance.

The term an “effective amount” of an agent, as used herein, is thatamount sufficient to effect beneficial or desired results, such asclinical results, and, as such, an “effective amount” depends upon thecontext in which it is being applied.

The terms “extended release” or “sustained release” interchangeablyrefer to a drug formulation that provides for gradual release of a drugover an extended period of time, e.g., 6-12 hours or more, compared toan immediate release formulation of the same drug. Preferably, althoughnot necessarily, results in substantially constant blood levels of adrug over an extended time period that are within therapeutic levels andfall within a peak plasma concentration range that is between, forexample, 0.05-10 μM, 0.1-10 μM, 0.1-5.0 μM, or 0.1-1 μM.

As used herein, the terms “formulated for enteric release” and “entericformulation” refer to pharmaceutical compositions, e.g., oral dosageforms, for oral administration able to provide protection fromdissolution in the high acid (low pH) environment of the stomach.Enteric formulations can be obtained by, for example, incorporating intothe pharmaceutical composition a polymer resistant to dissolution ingastric juices. In some embodiments, the polymers have an optimum pH fordissolution in the range of approx. 5.0 to 7.0 (“pH sensitivepolymers”). Exemplary polymers include methacrylate acid copolymers thatare known by the trade name Eudragit® (e.g., Eudragit® L100, Eudragit®S100, Eudragit® L-30D, Eudragit® FS 30D, and Eudragit® L100-55),cellulose acetate phthalate, cellulose acetate trimellitiate, polyvinylacetate phthalate (e.g., Coateric®), hydroxyethylcellulose phthalate,hydroxypropyl methylcellulose phthalate, or shellac, or an aqueousdispersion thereof. Aqueous dispersions of these polymers includedispersions of cellulose acetate phthalate (Aquateric®) or shellac(e.g., MarCoat 125 and 125N). An enteric formulation reduces thepercentage of the administered dose released into the stomach by atleast 50%, 60%, 70%, 80%, 90%, 95%, or even 98% in comparison to animmediate release formulation. Where such a polymer coats a tablet orcapsule, this coat is also referred to as an “enteric coating.”

By “immediate release” is meant that the agent (e.g., one of the TSPOcompounds), as formulated in a unit dosage form, has a dissolutionrelease profile under in vitro conditions in which at least 55%, 65%,75%, 85%, or 95% of the agent is released within the first two hours ofadministration to, e.g., a human. Desirably, the agent formulated in aunit dosage has a dissolution release profile under in vitro conditionsin which at least 50%, 65%, 75%, 85%, 90%, or 95% of the agent isreleased within the first 30 minutes, 45 minutes, or 60 minutes ofadministration.

The term “pharmaceutical composition,” as used herein, represents acomposition containing a compound described herein (e.g., an activatorof TSPO, or any pharmaceutically acceptable salt, solvate, clathrate,stereoisomer, enantiomer or prodrug thereof), formulated with apharmaceutically acceptable excipient, and typically manufactured orsold with the approval of a governmental regulatory agency as part of atherapeutic regimen for the treatment of disease in a mammal.Pharmaceutical compositions can be formulated, for example, for oraladministration in unit dosage form (e.g., a tablet, capsule, caplet,gelcap, or syrup); for topical administration (e.g., as a cream, gel,lotion, or ointment); for intravenous administration (e.g., as a sterilesolution free of particulate emboli and in a solvent system suitable forintravenous use); or in any other formulation described herein.

A “pharmaceutically acceptable excipient,” as used herein, refers anyingredient other than the compounds described herein (for example, avehicle capable of suspending or dissolving the active compound) andhaving the properties of being nontoxic and non-inflammatory in apatient. Excipients may include, for example: antiadherents,antioxidants, binders, coatings, compression aids, disintegrants, dyes(colors), emollients, emulsifiers, fillers (diluents), film formers orcoatings, flavors, fragrances, glidants (flow enhancers), lubricants,preservatives, printing inks, sorbents, suspensing or dispersing agents,sweeteners, or waters of hydration. Exemplary excipients include, butare not limited to: butylated hydroxytoluene (BHT), calcium carbonate,calcium phosphate (dibasic), calcium stearate, croscarmellose,cross-linked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine,ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, maltose,mannitol, methionine, methylcellulose, methyl paraben, microcrystallinecellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone,pregelatinized starch, propyl paraben, retinyl palmitate, shellac,silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodiumstarch glycolate, sorbitol, starch (corn), stearic acid, stearic acid,sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, andxylitol.

The term “pharmaceutically acceptable prodrugs” as used herein,represents those prodrugs of the compounds of the present inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theinvention.

The term “pharmaceutically acceptable salt,” as use herein, representsthose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and animalswithout undue toxicity, irritation, allergic response and the like andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention or separately by reacting the free base group with a suitableorganic or inorganic acid. Representative acid addition salts includeacetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptonate, glycerophosphate,hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride,hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,lauryl sulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like, as well asnontoxic ammonium, quaternary . ammonium, and amine cations, including,but not limited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like.

The terms “pharmaceutically acceptable solvate” or “solvate,” as usedherein, means a compound of the invention wherein: molecules of asuitable solvent are incorporated in the crystal lattice. A suitablesolvent is physiologically tolerable at the administered dose. Forexample, solvates may be prepared by crystallization, recrystallization,or precipitation from a solution that includes organic solvents, water,or a mixture thereof. Examples of suitable solvents are ethanol, water(for example, mono-, di-, and tri-hydrates), N-methylpyrrolidinone(NMP), dimethyl sulfoxide (DMSO), N,N′-dimethylformamide (DMF),N,N′-dimethylacetamide (DMAC), 1,3-dimethyl-2-imidazolidinone (DMEU),1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPU), acetonitrile(ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone,benzyl benzoate, and the like. When water is the solvent, the solvate isreferred to as a “hydrate.”

The term “prevent,” as used herein, refers to prophylactic treatment ortreatment that prevents one or more symptoms or conditions of a disease,disorder, or conditions described herein (e.g., chronic methamphetamineaddiction, a medical consequence of methamphetamine use, a behavioralconsequence of methamphetamine use, an HIV associated cognitive motordisorder, an HIV-associated neurodegenerative disorder, andneuroinflammation). Treatment can be initiated, for example, prior to(“pre-exposure prophylaxis”) or following (“post-exposure prophylaxis”)an event that precedes the onset of the disease, disorder, orconditions. Treatment that includes administration of a compound of theinvention, or a pharmaceutical composition thereof, can be acute,short-term, or chronic. The doses administered may be varied during thecourse of preventive treatment.

The term “prodrug,” as used herein, represents compounds which arerapidly transformed in vivo to the parent compound of the above formula.Prodrugs also encompass bioequivalent compounds that, when administeredto a human, lead to the in vivo formation of an activator of TSPO.

As used herein, and as well understood in the art, “treatment” is anapproach for obtaining beneficial or desired results, such as clinicalresults. Beneficial or desired results can include, but are not limitedto, alleviation or amelioration of one or more symptoms or conditions;diminishment of extent of disease, disorder, or condition; stabilized(i.e. not worsening) state of disease, disorder, or condition;preventing spread of disease, disorder, or condition; delay or slowingthe progress of the disease, disorder, or condition; amelioration orpalliation of the disease, disorder, or condition; and remission(whether partial or total), whether detectable or undetectable.“Treatment” can also mean prolonging survival as compared to expectedsurvival if not receiving treatment. As used herein, the terms“treating” and “treatment” can also refer to delaying the onset of,impeding or reversing the progress of, or alleviating either the diseaseor condition to which the term applies, or one or more symptoms of suchdisease or condition.

The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with anysuitable pharmaceutical excipient or excipients.

The present compounds can be prepared from readily available startingmaterials using the methods and procedures known in the art. It will beappreciated that where typical or preferred process conditions (i.e.,reaction temperatures, times, mole ratios of reactants, solvents,pressures, etc.) are given, other process conditions can also be usedunless otherwise stated. Optimum reaction conditions may vary with theparticular reactants or solvent used, but such conditions can bedetermined by one of ordinary skill in the art by routine optimizationprocedures.

Pharmaceutical Compositions The methods described herein can alsoinclude the administrations of pharmaceutically acceptable compositionsthat include an activator of TSPO, or a pharmaceutically acceptablesalt, solvate, clathrate, stereoisomer, enantiomer or prodrug thereof.Pharmaceutical compositions and dosage forms of the invention compriseone or more active ingredients in relative amounts and formulated sothat a given pharmaceutical composition or dosage form treatsmethamphetamine addiction and/or medical and/or behavioral consequencesof methamphetamine use and/or HIV infection. Preferred pharmaceuticalcompositions and dosage forms comprise a TSPO compound or apharmaceutically acceptable prodrug, salt, solvate, stereoisomer,enantiomer, or clathrate thereof, optionally in combination with one ormore additional active agents. When employed as pharmaceuticals, any ofthe present compounds can be administered in the form of pharmaceuticalcompositions. These compositions can be prepared in a manner well knownin the pharmaceutical art, and can be administered by a variety ofroutes, depending upon whether local or systemic treatment is desiredand upon the area to be treated. Administration may be topical,parenteral, intravenous, intra-arterial, subcutaneous, intramuscular,intracranial, intraorbital, ophthalmic, intraventricular, intracapsular,intraspinal, intracisternal, intraperitoneal, intranasal, aerosol, bysuppositories, or oral administration.

This invention also includes pharmaceutical compositions which cancontain one or more pharmaceutically acceptable carriers. In making thepharmaceutical compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semisolid, or liquid material (e.g., normal saline),which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of tablets, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,and soft and hard gelatin capsules. As is known in the art, the type ofdiluent can vary depending upon the intended route of administration.The resulting compositions can include additional agents, such aspreservatives.

The therapeutic agents of the invention (e.g. the TSPO compounds) can beadministered alone, combined, or in a mixture, in the presence of apharmaceutically acceptable excipient or carrier. The excipient orcarrier is selected on the basis of the mode and route ofadministration. Suitable pharmaceutical carriers, as well aspharmaceutical necessities for use in pharmaceutical formulations, aredescribed in Remington: The Science and Practice of Pharmacy, 21^(st)Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005), a well-knownreference text in this field, and in the USP/NF (United StatesPharmacopeia and the National Formulary). In preparing a formulation,the active compound can be milled to provide the appropriate particlesize prior to combining with the other ingredients. If the activecompound is substantially insoluble, it can be milled to a particle sizeof less than 200 mesh. If the active compound is substantially watersoluble, the particle size can be adjusted by milling to provide asubstantially uniform distribution in the formulation, e.g. about 40mesh.

Examples of suitable excipients are lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Otherexemplary excipients are described in Handbook of PharmaceuticalExcipients, 6^(th) Edition, Rowe et al., Eds., Pharmaceutical Press(2009).

The pharmaceutical compositions can be formulated so as to provideimmediate, extended, or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining, e.g., 0.1-500 mg of the active ingredient. For example, thedosages can contain from about 0.1 mg to about 50 mg, from about 0.1 mgto about 40 mg, from about 0.1 mg to about 20 mg, from about 0.1 mg toabout 10 mg, from about 0.2 mg to about 20 mg, from about 0.3 mg toabout 15 mg, from about 0.4 mg to about 10 mg, from about 0.5 mg toabout 1 mg; from about 0.5 mg to about 100 mg, from about 0.5 mg toabout 50 mg, from about 0.5 mg to about 30 mg, from about 0.5 mg toabout 20 mg, from about 0.5 mg to about 10 mg, from about 0.5 mg toabout 5 mg; from about 1 mg from to about 50 mg, from about 1 mg toabout 30 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10mg, from about 1 mg to about 5 mg; from about 5 mg to about 50 mg, fromabout 5 mg to about 20 mg, from about 5 mg to about 10 mg; from about 10mg to about 100 mg, from about 20 mg to about 200 mg, from about 30 mgto about 150 mg, from about 40 mg to about 100 mg, from about 50 mg toabout 100 mg of the active ingredient, from about 50 mg to about 300 mg,from about 50 mg to about 250 mg, from about 100 mg to about 300 mg, orfrom about 100 mg to about 250 mg of the active ingredient. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with one or more pharmaceutical excipients to form asolid bulk formulation composition containing a homogeneous mixture of acompound of the present invention. When referring to these bulkformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets and capsules. This solid bulk formulation is thensubdivided into unit dosage forms of the type described above containingfrom, for example, 0.1 to about 500 mg of the active ingredient of thepresent invention.

Compositions for Oral Administration. The pharmaceutical compositionscontemplated by the invention include those formulated for oraladministration (“oral dosage forms”). Oral dosage forms can be, forexample, in the form of tablets, capsules, a liquid solution orsuspension, a powder, or liquid or solid crystals, which contain theactive ingredient(s) in a mixture with non-toxic pharmaceuticallyacceptable excipients. These excipients may be, for example, inertdiluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol,microcrystalline cellulose, starches including potato starch, calciumcarbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate,or sodium phosphate); granulating and disintegrating agents (e.g.,cellulose derivatives including microcrystalline cellulose, starchesincluding potato starch, croscarmellose sodium, alginates, or alginicacid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginicacid, sodium alginate, gelatin, starch, pregelatinized starch,microcrystalline cellulose, magnesium aluminum silicate,carboxymethylcellulose sodium, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethyleneglycol); and lubricating agents, glidants, and antiadhesives (e.g.,magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenatedvegetable oils, or talc). Other pharmaceutically acceptable excipientscan be colorants, flavoring agents, plasticizers, humectants, bufferingagents, and the like.

Formulations for oral administration may also be presented as chewabletablets, as hard gelatin capsules wherein the active ingredient is mixedwith an inert solid diluent (e.g., potato starch, lactose,microcrystalline cellulose, calcium carbonate, calcium phosphate orkaolin), or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin, or olive oil. Powders, granulates, and pellets may be preparedusing the ingredients mentioned above under tablets and capsules in aconventional manner using, e.g., a mixer, a fluid bed apparatus or aspray drying equipment.

Controlled release compositions for oral use may be constructed torelease the active drug by controlling the dissolution and/or thediffusion of the active drug substance. Any of a number of strategiescan be pursued in order to obtain controlled release and the targetedplasma concentration vs time profile. In one example, controlled releaseis obtained by appropriate selection of various formulation parametersand ingredients, including, e.g., various types of controlled releasecompositions and coatings. Thus, the drug is formulated with appropriateexcipients into a pharmaceutical composition that, upon administration,releases the drug in a controlled manner. Examples include single ormultiple unit tablet or capsule compositions, oil solutions,suspensions, emulsions, microcapsules, microspheres, nanoparticles,patches, and liposomes. In certain embodiments, compositions includebiodegradable, pH, and/or temperature-sensitive polymer coatings.

Dissolution or diffusion controlled release can be achieved byappropriate coating of a tablet, capsule, pellet, or granulateformulation of compounds, or by incorporating the compound into anappropriate matrix. A controlled release coating may include one or moreof the coating substances mentioned above and/or, e.g., shellac,beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glycerylmonostearate, glyceryl distearate, glycerol palmitostearate,ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetatebutyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone,polyethylene, polymethacrylate, methylmethacrylate,2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol,ethylene glycol methacrylate, and/or polyethylene glycols. In acontrolled release matrix formulation, the matrix material may alsoinclude, e.g., hydrated methylcellulose, carnauba wax and stearylalcohol, carbopol 934, silicone, glyceryl tristearate, methylacrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/orhalogenated fluorocarbon.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally include aqueoussolutions, suitably flavored syrups, aqueous or oil suspensions, andflavored emulsions with edible oils such as cottonseed oil, sesame oil,coconut oil, or peanut oil, as well as elixirs and similarpharmaceutical vehicles.

Compositions suitable for oral mucosal administration (e.g., buccal orsublingual administration) include tablets, lozenges, and pastilles,where the active ingredient is formulated with a carrier, such as sugar,acacia, tragacanth, or gelatin and glycerine.

Coatings: The pharmaceutical compositions formulated for oral delivery,such as tablets or capsules of the present invention can be coated orotherwise compounded to provide a dosage form affording the advantage ofdelayed or extended release. The coating may be adapted to release theactive drug substance in a predetermined pattern (e.g., in order toachieve a controlled release formulation) or it may be adapted not torelease the active drug substance until after passage of the stomach,e.g., by use of an enteric coating (e.g., polymers that are pH-sensitive(“pH controlled release”), polymers with a slow or pH-dependent rate ofswelling, dissolution or erosion (“time-controlled release”), polymersthat are degraded by enzymes (“enzyme-controlled release” or“biodegradable release”) and polymers that form firm layers that aredestroyed by an increase in pressure (“pressure-controlled release”)).Exemplary enteric coatings that can be used in the pharmaceuticalcompositions described herein include sugar coatings, film coatings(e.g., based on hydroxypropyl methylcellulose, methylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose,acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone),or coatings based on methacrylic acid copolymer, cellulose acetatephthalate, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, shellac,and/or ethylcellulose. Furthermore, a time delay material such as, forexample, glyceryl monostearate or glyceryl distearate, may be employed.

For example, the tablet or capsule can comprise an inner dosage and anouter dosage component, the latter being in the form of an envelope overthe former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease.

When an enteric coating is used, desirably, a substantial amount of thedrug is released in the lower gastrointestinal tract.

In addition to coatings that effect delayed or extended release, thesolid tablet compositions may include a coating adapted to protect thecomposition from unwanted chemical changes (e.g., chemical degradationprior to the release of the active drug substance). The coating may beapplied on the solid dosage form in a similar manner as that describedin Encyclopedia of Pharmaceutical Technology, vols. 5 and 6, Eds.Swarbrick and Boyland, 2000.

Parenteral Administration: Within the scope of the present invention arealso parenteral depot systems from biodegradable polymers. These systemsare injected or implanted into the muscle or subcutaneous tissue andrelease the incorporated drug over extended periods of time, rangingfrom several days to several months. Both the characteristics of thepolymer and the structure of the device can control the release kineticswhich can be either continuous or pulsatile. Polymer-based parenteraldepot systems can be classified as implants or microparticles. Theformer are cylindrical devices injected into the subcutaneous tissuewhereas the latter are defined as spherical particles in the range of10-100 μm. Extrusion, compression or injection molding are used tomanufacture implants whereas for microparticles, the phase separationmethod, the spray-drying technique and the water-in-oil-in-wateremulsion techniques are frequently employed. The most commonly usedbiodegradable polymers to form microparticles are polyesters from lacticand/or glycolic acid, e.g. poly(glycolic acid) and poly(L-lactic acid)(PLG/PLA microspheres). Of particular interest are in situ forming depotsystems, such as thermoplastic pastes and gelling systems formed bysolidification, by cooling, or due to the sol-gel transition,cross-linking systems and organogels formed by amphiphilic lipids.Examples of thermosensitive polymers used in the aforementioned systemsinclude, N-isopropylacrylamide, poloxamers (ethylene oxide and propyleneoxide block copolymers, such as poloxamer 188 and 407), poly(N-vinylcaprolactam), poly(siloethylene glycol), polyphosphazenes derivativesand PLGA-PEG-PLGA.

Mucosal Drug Delivery: Mucosal drug delivery (e.g., drug delivery viathe mucosal linings of the nasal, rectal, vaginal, ocular, or oralcavities) can also be used in the methods described herein. Methods fororal mucosal drug delivery include sublingual administration (viamucosal membranes lining the floor of the mouth), buccal administration(via mucosal membranes lining the cheeks), and local delivery (Harris etal., Journal of Pharmaceutical Sciences, 81(1): 1-10, 1992)

Oral transmucosal absorption is generally rapid because of the richvascular supply to the mucosa and allows for a rapid rise in bloodconcentrations of the therapeutic (“American Academy of Pediatrics:Alternative Routes of Drug Administration—Advantages and Disadvantages(Subject Review),” Pediatrics, 100(1): 143-152, 1997).

For buccal administration, the compositions may take the form of, e.g.,tablets, lozenges, etc. formulated in a conventional manner. Permeationenhancers can also be used in buccal drug delivery. Exemplary enhancersinclude 23-lauryl ether, aprotinin, azone, benzalkonium chloride,cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrin,dextran sulfate, lauric acid, lysophosphatidylcholine, methol,methoxysalicylate, methyloleate, oleic acid, phosphatidylcholine,polyoxyethylene, polysorbate 80, sodium EDTA, sodium glycholate, sodiumglycodeoxycholate, sodium lauryl sulfate, sodium salicylate, sodiumtaurocholate, sodium taurodeoxycholate, sulfoxides, and alkylglycosides. Bioadhesive polymers have extensively been employed inbuccal drug delivery systems and include cyanoacrylate, polyacrylicacid, hydroxypropyl methylcellulose, and poly methacrylate polymers, aswell as hyaluronic acid and chitosan.

Liquid drug formulations (e.g., suitable for use with nebulizers andliquid spray devices and electrohydrodynamic (EHD) aerosol devices) canalso be used. Other methods of formulating liquid drug solutions orsuspension suitable for use in aerosol devices are known to those ofskill in the art.

Formulations for sublingual administration can also be used, includingpowders and aerosol formulations. Exemplary formulations include rapidlydisintegrating tablets and liquid-filled soft gelatin capsules.

Dosing Regimens: The present methods for treating methamphetamineaddiction and medical and behavioral consequences of methamphetamine useand HIV infection, including neuroinflammation, are carried out byadministering one or more TSPO compounds for a time and in an amountsufficient to result in stabilization and/or reversal of the symptoms ofmethamphetamine addiction and medical and behavioral consequences ofmethamphetamine use and HIV infection, including neuroinflammation.

The amount and frequency of administration of the compositions can varydepending on, for example, what is being administered, the state of thepatient, and the manner of administration. The dosage is likely todepend on such variables as the type and extent of progression of themethamphetamine addiction, HIV infection, or neuroinflammation, theseverity of the medical and behavioral consequences of methamphetamineuse and HIV infection, or neuroinflammation, the age, weight and generalcondition of the particular patient, the relative biological efficacy ofthe composition selected, formulation of the excipient, the route ofadministration, and the judgment of the attending clinician. Effectivedoses can be extrapolated from dose-response curves derived from invitro or animal model test system. An effective dose is a dose thatproduces a desirable clinical outcome by, for example, improving a signor symptom of chronic tissue ischemia or slowing its progression.

The amount of TSPO compound per dose can vary. For example, a subjectcan receive from about 0.1 μg/kg to about 10,000 μg/kg. Generally, theTSPO compound is administered in an amount such that the peak plasmaconcentration ranges from 150 nM-250 μM.

Exemplary dosage amounts can fall between 0.1-5000 μg/kg, 100-1500μg/kg, 100-350 μg/kg, 340-750 μg/kg, or 750-1000 μg/kg. Exemplarydosages can 0.25, 0.5, 0.75, 1°, or 2 mg/kg. In another embodiment, theadministered dosage can range from 0.05-5 mmol of TSPO compound (e.g.,0.089-3.9 mmol) or 0.1-50 μmol of TSPO compound (e.g., 0.1-25 μmol or0.4-20 μmol).

The frequency of treatment may also vary. The subject can be treated oneor more times per day with a TSPO compound (e.g., once, twice, three,four or more times) or every so-many hours (e.g., about every 2, 4, 6,8, 12, or 24 hours). Preferably, the pharmaceutical composition isadministered 1 or 2 times per 24 hours. The time course of treatment maybe of varying duration, e.g., for two, three, four, five, six, seven,eight, nine, ten or more days. For example, the treatment can be twice aday for three days, twice a day for seven days, twice a day for tendays. Treatment cycles can be repeated at intervals, for example weekly,bimonthly or monthly, which are separated by periods in which notreatment is given. The treatment can be a single treatment or can lastas long as the life span of the subject (e.g., many years).

KITS: Any of the pharmaceutical compositions of the invention describedherein can be used together with a set of instructions, i.e., to form akit. The kit may include instructions for use of the pharmaceuticalcompositions as a therapy as described herein. For example, theinstructions may provide dosing and therapeutic regimes for use of thecompounds of the invention to reduce incidence, duration, and orseverity of methamphetamine addiction, medical and behavioralconsequences of methamphetamine use and HIV infection, orneuroinflammation.

Various objects, features, aspects, and advantages of the presentinvention will become more apparent from the following detaileddescription of preferred embodiments of the invention, along with theaccompanying drawings in which like numerals represent like components.The present invention may address one or more of the problems anddeficiencies of the current technology discussed above. However, it iscontemplated that the invention may prove useful in addressing otherproblems and deficiencies in a number of technical areas. Therefore theclaimed invention should not necessarily be construed as limited toaddressing any of the particular problems or deficiencies discussedherein.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of the specification, illustrate various embodiments of theinvention and together with the general description of the inventiongiven above and the detailed description of the drawings given below,serve to explain the principles of the invention. It is to beappreciated that the accompanying drawings are not necessarily to scalesince the emphasis is instead placed on illustrating the principles ofthe invention. The invention will now be described, by way of example,with reference to the accompanying drawings in which:

FIGS. 1A-1E are diagrams of four benzodiazepine ligands (FIGS. 1A-1D),and a diagram and table of structure-activity relationships forelements/compounds in the 1,2′, 3, 4′ and 7 positions on the ligands(FIG. 1E);

FIGS. 2A-2B are two graphs showing the effects of oxazepam (OX) andalprazolam (ALP) on drug discrimination, where alprazolam enhancedlow-dose methamphetamine discrimination (FIG. 2A) but did not affectcocaine discrimination (FIG. 2B), and oxazepam decreased thediscriminative stimulus effects of both MA and cocaine (FIGS. 2A and2B);

FIG. 3 is a graph that shows the effects of oxazepam and alprazolam onmethamphetamine self-administration, where alprazolam (4 mg) enhancedlow dose methamphetamine self-administration and oxazepam decreasedmethamphetamine self-administration responding at all doses tested;

FIG. 4 is bar graph showing the effects of oxazepam and alprazolam onmethamphetamine induced reinstatement, where alprazolam enhanced lowdose methamphetamine-induced reinstatement and oxazepam decreasedmethamphetamine-induced reinstatement at all doses tested;

FIGS. 5A-5B are two bar graphs showing receptor dependence of oxazepamand alprazolam effects on methamphetamine self-administration, showingalprazolam enhanced low dose methamphetamine self-administration (FIG.5A) and was blocked by flumazenil, and oxazepam decreased standard dosemethamphetamine self-administration (FIG. 5B) and was partially blockedby PK11195 and flumazenil, and that oxazepam had no effect on low-dosemethamphetamine self-administration (FIG. 5A);

FIG. 6 is bar graph showing the effects of Ro5-4864, oxazepam andalprazolam on methamphetamine self-administration with male rats; and

FIG. 7 is bar graph showing the effects of Ro5-4864, Ro7-9277, oxazepamand alprazolam on methamphetamine self-administration with female rats,showing females of the species appear to be significantly more sensitiveto the effects of Ro5-4864 compared to the males of the species.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention will be understood by reference to the followingdetailed description, which should be read in conjunction with theappended drawings. It is to be appreciated that the following detaileddescription of various embodiments is by way of example only and is notmeant to limit, in any way, the scope of the present invention. In thesummary above, in the following detailed description, in the claimsbelow, and in the accompanying drawings, reference is made to particularfeatures (including method steps) of the present invention. It is to beunderstood that the disclosure of the invention in this specificationincludes all possible combinations of such particular features, not justthose explicitly described. For example, where a particular feature isdisclosed in the context of a particular aspect or embodiment of theinvention or a particular claim, that feature can also be used, to theextent possible, in combination with and/or in the context of otherparticular aspects and embodiments of the invention, and in theinvention generally. The term “comprises” and grammatical equivalentsthereof are used herein to mean that other components, ingredients,steps, etc. are optionally present. For example, an article “comprising”(or “which comprises”) components A, B, and C can consist of (i.e.,contain only) components A, B, and C, or can contain not only componentsA, B, and C but also one or more other components. Where reference ismade herein to a method comprising two or more defined steps, thedefined steps can be carried out in any order or simultaneously (exceptwhere the context excludes that possibility), and the method can includeone or more other steps which are carried out before any of the definedsteps, between two of the defined steps, or after all the defined steps(except where the context excludes that possibility).

The term “at least” followed by a number is used herein to denote thestart of a range beginning with that number (which may be a range havingan upper limit or no upper limit, depending on the variable beingdefined). For example “at least 1” means 1 or more than 1. The term “atmost” followed by a number is used herein to denote the end of a rangeending with that number (which may be a range having 1 or 0 as its lowerlimit, or a range having no lower limit, depending upon the variablebeing defined). For example, “at most 4” means 4 or less than 4, and “atmost 40% means 40% or less than 40%. When, in this specification, arange is given as “(a first number) to (a second number)” or “(a firstnumber)-(a second number),” this means a range whose lower limit is thefirst number and whose upper limit is the second number. For example, 25to 100 mm means a range whose lower limit is 25 mm, and whose upperlimit is 100 mm. The embodiments set forth the below represent thenecessary information to enable those skilled in the art to practice theinvention and illustrate the best mode of practicing the invention. Inaddition, the invention does not require that all the advantageousfeatures and all the advantages need to be incorporated into everyembodiment of the invention.

Turning now to FIGS. 1-5, a brief description concerning the variouscomponents of the present invention will now be briefly discussed.

Benzodiazepines and psychostimulant abuse: Benzodiazepines (BZDs) canbind to two distinct binding sites: GABA_(A) receptors and theTSPO—Oxazepam and other benzodiazepines can increase inhibitoryconductance and decrease neuronal excitability by binding to theGABA_(A) receptor at the benzodiazepine positive allosteric modulatorysite. By increasing the affinity of GABA for the receptor,benzodiazepine agonists increase the frequency of channel opening andfacilitate the influx of chloride ions, resulting in a hyperpolarizationof the membrane and decreased action potential propagation. Thisclassical mechanism of action applies to nearly all benzodiazepines,including alprazolam and oxazepam. However, some benzodiazepines alsohave a high affinity for a second binding site, formerly known as theperipheral benzodiazepine receptor. As described above, this protein isnow known as the TSPO and has a distinct pharmacology and subcellularlocalization when contrasted with the GABA_(A) receptor. Importantly,many benzodiazepines, most notably diazepam and midazolam, bind to andactivate the TSPO to increase neurosteroid biosynthesis. The TSPO isresponsible for catalyzing the first steps of steroidogenesis bytranslocating cholesterol from the cytoplasm into the mitochondrialmatrix. This allows cholesterol side-chain cleavage enzyme (CYP11A1;also known as P450scc) to convert cholesterol to pregnenolone, the firstenzymatic conversion in the steroid biosynthesis cascade. As shown inFIG. 1, structure-activity relationships evidence that oxazepam binds toboth GABA_(A) receptors and the TSPO.

Structurally, oxazepam is nearly identical to diazepam, a prototypicalagonist of both GABA_(A) receptors and the TSPO, suggesting thatoxazepam may increase neurosteroid levels by activating the TSPO. Thisis in contrast to alprazolam, a benzodiazepine that binds selectively tothe GABA_(A) receptor and exhibits low affinity for the TSPO. Subsequentex vivo homogenate binding assays have confirmed the inventors'hypothesis in rat brain tissue.

Benzodiazepines affect cocaine and methamphetamine-related behaviorsdifferently—The inventors' laboratory has long been interested in therole for benzodiazepines in drug addiction. Early research demonstratedthat chronic cocaine exposure differentially affects the density ofbenzodiazepine receptors across several brain regions, an effect that isdependent on intact dopaminergic signaling. Additional research showedthat several benzodiazepine receptor agonists could decrease cocainerelated behaviors, including chlordiazepoxide, alprazolam, and oxazepam.

However, evidence from the inventors' laboratory demonstrated thatoxazepam and alprazolam differentially affect the discriminativestimulus effects of cocaine and methamphetamine in female rats. Adultfemale Wistar rats were trained to discriminate 1 mg/kg methamphetamine(IP) from saline using food pellet reinforcement according to previouslypublished procedures (Mantsch and Goeders, 1999, 1998). Pretreatmentwith alprazolam (4 mg/kg, IP) enhanced the methamphetaminediscriminative stimulus at doses of 0.125 and 0.25 mg/kgmethamphetamine. As shown in FIGS. 2A and 2B, pretreatment withalprazolam had no effect on cocaine discrimination. However,pretreatment with oxazepam dose-dependently decreased the discriminativestimulus effects of both cocaine and methamphetamine .These results weresupported by additional findings from the inventors' laboratory wherebyoxazepam and alprazolam altered cocaine and methamphetamineself-administration in remarkably different ways. In male rats trainedto self-administer methamphetamine (0.06 mg/kg/infusion), pretreatmentwith alprazolam (4 mg/kg, IP) resulted in significant increases in theself-administration of very low doses of the drug. On the other hand, asshown in FIG. 3, pretreatment with only oxazepam produced significantdecreases in methamphetamine self-administration across all doses. Theseobservations have been confirmed using a conditioned place preferencemodel as well, evidencing that benzodiazepines differentially modulatethe rewarding and reinforcing properties of methamphetamine. These datawere further supported by a drug-induced reinstatement (D-IR) study. Inthe D-IR study, as shown in FIG. 4, oxazepam decreasedmethamphetamine-induced reinstatement while alprazolam actuallypotentiated the ability of a low-dose priming injection ofmethamphetamine to induce reinstatement. Thus, this is anextraordinarily consistent pattern across three very different models ofdrug-related behaviors. On the other hand, both oxazepam and alprazolamreduce cocaine-related behaviors in a similar manner.

The inventors conclude, based on such evidence, that the differenteffects between oxazepam and alprazolam stem from their differentialbinding to GABA_(A) receptors and to the TSPO, and that thesedifferences especially impact their actions on methamphetaminepharmacology.

Some effects of oxazepam and alprazolam on the subjective effects ofd-amphetamine and methamphetamine have previously been reported, whichat first blush appear to contradict the inventors finding. In contrastto the inventors' findings in rats, Rush and colleagues reported thatalprazolam administration reduced some of the subjective effects of themethamphetamine “high” while oxazepam had no significant effect on thesubjective effects of d-amphetamine (Lile et al., 2011, 2005). Thedifferences between those results in humans and the inventors' data inrats are likely a result of the doses used as well as the differences inpharmacokinetics due to the route of administration. For example,significant differences are observed in the time to maximummethamphetamine concentrations in the blood (T_(max)) of humans whencomparing intravenously administered methamphetamine (i.e., 6±11 min) tosmoked (150±30 min), oral (216 min; range 180-300 min) or intranasaladministration (169±8 min). In contrast, the T_(max) for intraperitonealmethamphetamine injections in rats is 7.5±2.8 min, which is notsignificantly different from that measured following intravenousmethamphetamine administration. Methamphetamine (or d-amphetamine) wasadministered intra-nasally or orally in the human studies, suggestingthat T_(max) would not have been reached in the Rush experiments as itwas in the inventors' rat studies. In addition, in the Rush experimentsthe benzodiazepines were administered acutely at the same time asamphetamine, and oxazepam may not have had sufficient time to reachmaximum blood levels as it is more slowly absorbed compared toalprazolam. Finally, the doses of d-amphetamine or methamphetaminetested in the human studies (i.e., up to 30 mg) were quite low.Intravenous methamphetamine users are known to inject doses as high as250 mg at a time. Thus, the lack of reproducibility between theinventors' studies and those Rush conducted in humans are likely due tofactors (e.g., dose, route of administration) that may be limited in thehuman laboratory due to ethical considerations, but such laboratoryconditions may not be representative of the manner in which a typicalhuman methamphetamine user actually uses methamphetamine.

The inventors are aware that oxazepam is one of the least desirablebenzodiazepines by drug-dependent individuals. In contrast, alprazolamis consistently related as one of the most desired benzodiazepines bydrug-dependent individuals. This difference between oxazepam andalprazolam is one of the reasons that the inventors have recentlyfocused on oxazepam for its potential in treating drug-dependentsubjects. The inventors conclude, based on the experimental evidence,that the differences in abuse liability between oxazepam and alprazolamstem from their differential interactions with GABA_(A) receptors andthe TSPO.

Such experiments include those to assess the receptors potentiallyresponsible for the effects of oxazepam and alprazolam onmethamphetamine self-administration in rats. When administered 30minutes prior to alprazolam, the GABA_(A) receptor antagonist flumazenilinhibited the effects of alprazolam on low-dose methamphetamineself-administration, suggesting a primary role of GABA_(A) receptors.However, as shown in FIGS. 5A and 5B, oxazepam's effects onmethamphetamine self-administration were also blocked by the TSPOantagonist, PKII195 in male rats, suggesting a central role for TSPObinding in the effects of oxazepam on methamphetamine-related behaviors.

Psychomotor stimulants and TSPO binding—The chronic administration ofamphetamine derivatives results in significant microglial activation andproliferation. This injury can be monitored using imaging or bindingtechniques to analyze the up regulation of the TSPO. TSPO levels havebeen used as an indirect quantitative measure of microglial activationfollowing chemically-induced brain insults, and the concomitantmicroglial activation has been employed as a marker of specificneurotoxic amphetamine-related damage. Subchronic, repeated doses ofmethamphetamine (4×10 mg/kg SC, every two hours) increase TSPO bindingin the striatum, cerebellum and hippocampus within 72 hours.Self-administration of methamphetamine (0.3 mg/kg/inf) also enhancesTSPO binding. Withdrawal from methamphetamine (1.0 mg/kg, IP, twice perday for 2 weeks, withdrawn for 7 days) also enhances TSPO mRNA in rats.This increase in TSPO is used as an indirect measure ofneuroinflammation/microgliosis. A genetic knockout of IL-6, a majorinflammatory factor, can attenuate the increased glial response tomethamphetamine. Human methamphetamine users also display increases inTSPO binding measured using positron emission tomography (PET) imaging.This increased TSPO binding has also been correlated with the durationof methamphetamine use and abstinence. Methamphetamine has also beendemonstrated to increase glial fibrillary acidic protein (GFAP)immunoreactivity, a well-established histopathological marker of glialactivation and neuroinflammation.

TSPO, neurosteroids and neuroinflammation: TSPO agonists increaseneurosteroid biosynthesis—One of the primary advantages to TSPO-favoringbenzodiazepines is the downstream effects of TSPO activation. TSPOagonism induces changes in intracellular cholesterol trafficking such topromote the biosynthesis of several important steroid metabolites,including progesterone and allopregnanolone. These “neurosteroids” havefast actions on ion channels such as the GABA_(A) receptor and are ableto affect neuronal excitability in a paracrine manner. Neurosteroidssuch as allopregnanolone and tetrahydrodeoxycorticosterone (THDOC) arepositive allosteric modulators at different GABA_(A) receptor bindingsites compared to benzodiazepines. TSPO agonism has been shown to beclinically relevant in anxiety and pain disorders, with no tolerance orwithdrawal as seen with benzodiazepine treatment.

TSPO agonists and neurosteroids reduceneuroinflammation/neurodegeneration—TSPO ligands possessanti-inflammatory properties. This action may be mediated by modulationof mitochondrial function. Neurosteroids such as allopregnanolone andprogesterone also possess neuroprotective and anti-inflammatoryproperties. The levels of these neurosteroids are altered byneurodegenerative processes and therefore, neurosteroids have becometherapeutic candidates for many disorders. Allopregnanolone reducestraumatic brain injury-associated changes in inflammatory and apoptoticmarkers. Allopregnanolone also decreases neuronal loss in a number ofneurodegenerative disorders including Parkinson's disease, Alzheimer'sdisease and amyotrophic lateral sclerosis. As discussed above, prolongedmethamphetamine exposure enhances neuroinflammatory responses in rodentbrains including enhanced GFAP expression and activated microglialphenotypes. This evidences that pharmacotherapies for methamphetamineabuse use should include compounds that affect neuroinflammation,including neurosteroids and TSPO ligands.

Neurosteroids reduce drug abuse and related deficits—Neurosteroids suchas allopregnanolone may hold promise as pharmacological treatments fordrug addiction as well. Allopregnanolone has been demonstrated todecrease methamphetamine-related responding in female rats as well ascocaine-related responding in both genders. Combining theanti-inflammatory properties and reward-decreasing properties ofneurosteroids is another novel and innovative way to treat the cognitiveand behavioral deficits associated with chronic methamphetamine abuse.

Thus, the inventors propose a novel approach for treating not onlyaddiction to methamphetamine but also the medical (e.g.,neuroinflarnrnation and cognitive deficits) and behavioral consequencesof chronic methamphetamine exposure. Using benzodiazepine classcompounds that modulate specific methamphetamine-induced behaviorsand/or neuropathology are a novel pharmacotherapeutic treatment formethamphetamine. Targeting TSPO is an overlooked mechanism of action.Modulating a glial-based pharmacological target (i.e., the TSPO) is anovel treatment for neuropsychiatric disorders.

The inventors' research has demonstrated that certain specificbenzodiazepine-related drugs can powerfully reducemethamphetamine-related behaviors in rats, a finding which the dataevidences is related to benzodiazepine-induced TSPO activation. Otherbenzodiazepines may also activate TSPO and, therefore, based on suchproperty would be useful in reducing methamphetamine-related behaviors.In further research, a further TSPO, Ro5-4864, was shown to also affectmethamphetamine self-administration.

Structure-activity relationships evidence that benzodiazepines with ahalogen moiety in the 4′ position (i.e., bound to the 4′ carbon—seegeneric benzodiazepine and affinity table above) possess higher affinityfor TSPO and a much lower affinity for the GABA_(A) receptor. Namely,compounds with the basic benzodiazepine structure, but with a halogenmoiety (e.g., chlorine, fluorine, bromine, iodine) in the 4′ positioninstead of the normal hydrogen. These compounds are referred to hereinas TSPO compounds. Several drug compounds that meet such criteria aredescribed in the table below.

Binding Affinity Table

Pos TSPO GABA 1 CH3 >> H H = CH3 7 Cl >F >> NO2 Cl = NO2 > F 4′ Cl > F >OCH3 >> NO2 H > OH >> Cl > F 2′ Cl > F > H Cl > F > H 3 OH > H H > OH

Example TSPO Compounds Structural Position Drug 1 7 4′ 2′ 3 6′ 4Ro5-5115 CH3 H Cl H H H — Ro5-5119 CH3 H Cl H H H CH3 Ro5-5120 CH3 NO2Cl H H H — Ro5-5122 CH3 H F H H H — Ro5-5888 CH3 Cl Cl H H H H Ro5-4864CH3 Cl Cl H H H — Ro5-6524 CH3 F Cl H H H CH3 Ro5-6528 CH3 F Cl H H H HRo5-6531 CH3 F Cl H H H — Ro5-6900 CH3 Cl Cl CI H H — Ro5-6902 CH3 Cl ClH H H H Ro5-6945 CH2CH═CH2 Cl Cl H H H — Ro5-6993 CH2CH3 Cl Cl H H H —Ro7-9277 CH3 Cl Cl H OH H —

The structural names (and Chemical Abstracts Service Registry numbers or“CAS #” where available) for the above compounds and otherbenzodiazepine ligands shown in FIGS. 1A-1D are listed in the tablebelow:

Compound Structure CAS # Ro5-51154′-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one N/ARo5-51194′-chloro-1,3-dihydro-1,4-dimethyl-5-phenyl-2H-1,4-benzodiazepin-2-oneN/A Ro5-51204′-chloro-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-oneN/A Ro5-51224′-Fluoro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one N/ARo5-58884′,7-Dichloro-1,3,4-trihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneN/A Ro5-48644′,7-Dichloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneN/A Ro5-65244′-Chloro-7-fluoro-1,3-dihydro-1,4-dimethyl-5-phenyl-2H-1,4-benzodiazepin-2-oneN/A Ro5-65284′-Chloro-7-fluoro-1,3,4-trihydro-1,4-dimethyl-5-phenyl-2H-1,4-benzodiazepin-2-oneN/A Ro5-65314′-Chloro-7-fluoro-1,3-dihydro-1-methy1-5-pheny1-2H-1,4-benzodiazepin-2-oneN/A Ro5-69002′,4′,7-trichloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneN/A Ro5-69024′,6′,7-Trichloro-1,3,4-trihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneN/A Ro5-69451-allyl-4′,7-dichloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-oneN/A Ro5-69934′,7-dichloro-1-ethyl-1′3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-oneN/A Ro7-92774′,7-dichloro-1-hydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-oneN/A Diazepam7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one439-14-5 Oxazepam7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one604-75-1 Alprazolam8-chloro-1-methyl-5-phenyl-4H-(1,2,4)triazolo-1,4-benzodiazepine28981-97-7

Turning to FIGS. 6 and 7, the inventors tested the TSPO compoundRo5-4864 in an animal model of methamphetamine self-administration inmale and female rats. The experiments demonstrated a dose-relateddecrease in methamphetamine self-administration confirming a role forTSPO in methamphetamine reward. These data suggest that the TSPO may bea viable target for methamphetamine dependence. The inventors comparedthese effects to the effects of the benzodiazepine alprazolam. Ro5-4864may be superior to alprazolam due to the abuse potential of alprazolam.As shown in FIG. 7 female rats appear to be significantly more sensitiveto the effects of Ro5-4864 compared to male rats. The inventors alsoshow preliminary data with Ro7-9277 with female rats.

Based on the experimental results, the inventors propose the use of theTSPO compounds to decrease methamphetamine-seeking andmethamphetamine-taking behaviors by decreasing the activation of braincircuits involved in methamphetamine craving. The inventors also proposethe use of the TSPO compounds to reduce other cognitive and behavioraleffects of methamphetamine. Methamphetamine users often exhibitneurocognitive impairments and are more likely to engage in risky sexualbehaviors that promote sexual-transmitted infections such as HIV.Chronic methamphetamine use and HIV infection both induce aneuroinflammatory response characterized by a marked increase in TSPObinding and microglial activation. TSPO activation decreases sexualbehavior and enhances memory functions, especially in animal models ofneuroinflammation or neurodegeneration. Therefore, targeting TSPOactivation as part of such treatment will decrease the neuroinflammatoryresponse and alleviate the neurocognitive effects associated withprolonged methamphetamine use. While the treatment is evidenced to beeffective for both males and females, one target patient group ismethamphetamine addicted females. The higher sensitivity of females toRo5-4864 further underscores females as a target patent group for thistreatment.

The inventors propose treatment of methamphetamine users and HIVinfected individuals with the TSPO compounds. Ro5-4864 is a prototypeTSPO compound which was shown to have does responsive effects. Based onexperimental evidence the inventors concluded that TSPO compounds reducecraving (or seeking) for methamphetamine, substantially halt and can atleast partially reverse the cognitive deficits produced bymethamphetamine use, and reduce the incidence of increased risky sexualbehaviors induced by methamphetamine. By reducing the occurrence ofmethamphetamine-induced sexual behaviors, and by decreasing theneuroinflammatory response associated with HIV, TSPO compounds could beone strategy used to reduce the consequences of HIV/AIDS inmethamphetamine users.

The invention includes pharmaceutical compositions comprising a TSPOcompound acting as a peripheral benzodiazepine receptor ligand incombination with one or more compatible pharmaceutically acceptableadjuvants or diluents which may be inert or physiologically active.These compositions may be administered by the oral, parenteral or rectalroute or locally. The TSPO compound acting as a peripheralbenzodiazepine receptor ligand may be may be selected from the groupincluding Ro5-5115, Ro5-5119, Ro5-5120, Ro5-5122, Ro5-5888, Ro5-4864,Ro5-6524, Ro5-6528, Ro5-6531, Ro5-6900, Ro5-6902, Ro5-6945, Ro5-6993,Ro7-9277, and oxazepam, for example, and therapeutically acceptablesalts, solvates, clathrates, stereoisomers, enantiomers or prodrugs ofthese compounds or mixtures thereof.

Other classes of drugs which would potentiate the actions of TSPOcompounds when used in combination with the TSPO compounds are agonists(activators) of potassium-chloride co-transporter 2 (KCC2) andinhibitors (antagonists) of 20 alpha-hydroxysteroid dehydrogenase (20alpha-HSD). A combination of TSPO with one or more agonists of KCC2 andone or more inhibitors of 20 alpha-HSD may also be used.

Agonists (activators) of potassium-chloride co-transporter 2 (KCC2)—

These compounds activate the chloride extrusion pump in neurons (KCC2)to modify the driving force for chloride ions across the neuronalmembrane. The inventors have observed that KCC2 agonists enhance theactivity of other GABAergic drugs, including neurosteroids andbenzodiazepines. Therefore, it follows that the combination of KCC2agonist and TSPO compound would enhance therapeutic effects byincreasing the efficacy of downstream signaling events includingGABA-gated chloride influx. Specific KCC2 activators could includeCLP257[(5Z)-5-[(4-Fluoro-2-hydroxyphenyl)methylene]-2-(tetrahydro-1-(2H)-pyridazinyl)-4(5H)-thiazolone].

Inhibitors (antagonists) of 20 alpha-hydroxysteroid dehydrogenase (20alpha-HSD)—This enzyme is responsible for the catabolism of GABA-activeactive neurosteroids. It follows that a combination of 20 alpha-HSDinhibitor and TSPO compound would further enhance the levels oftherapeutic neurosteroids by both enhancing the early steps ofneurosteroid biosynthesis and preventing enzymatic breakdown by 20alpha-HSD. Specific 20 alpha-HSD inhibitors could include STZ26(D-homo-16-oxa-4-androstene-3,16alpha-dione), 3-chloro-5-phenylsalicylicacid and 3-bromo-5-phenylsalicylic acid.

Tablets, pills, powders (gelatin capsules or cachets) or granules may beused as solid compositions for oral administration. In thesecompositions, the active ingredient according to the invention may bemixed with one or more inert diluents such as starch, cellulose,sucrose, lactose or silica. These compositions may also containsubstances other than diluents, for example one or more lubricants suchas magnesium stearate or talcum, a colorant, a coating (dragees) or alacquer.

Pharmaceutically acceptable solutions, suspensions, emulsions, syrupsand elixirs containing inert diluents such as water, ethanol, glycerol,benzoic acid, benzyl alcohol, sodium benzoate, dimethyl sulfoxide,vegetable oils or liquid paraffin may be used as liquid compositions fororal administration. These compositions may contain substances otherthan diluents, for example wetting agents, sweeteners, thickeners,flavoring agents or stabilizers.

Sterile compositions for parenteral administration may preferably benon-aqueous solutions, suspensions or emulsions. Water, propyleneglycol, polyethylene glycol, benzoic acid, benzyl alcohol, sodiumbenzoate, dimethyl sulfoxide, vegetable oils, especially olive oil,injectable organic acids esters, for example ethyl oleate or othersuitable organic solvents may be used as the solvent or the carrier.

These compositions may also contain adjuvants, especially wettingagents, tonicity regulating agents, emulsifiers, dispersants andstabilizers. The sterilization may be carried out in several ways, forexample by aseptic filtration, incorporating a sterilizing agent, byirradiation or by heating. They may also be prepared in the form ofsterile solid compositions which may be dissolved at the time of use ina sterile medium suitable for injection.

Compositions for rectal administration are suppositories or rectalcapsules, which contain, in addition to the active product, excipientssuch as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Compositions for local administration may be for example creams,ointments, lotions, eye lotions, mouthwashes, nasal drops or aerosols.

The dosage depends on the effect sought, the length of treatment and theadministration route employed. In general, the medical practitioner willdetermine the appropriate dosage depending on the age, weight and allother factors specific to the subject to be treated. The compositionswould preferably be administered similar to other clinically-relevantbenzodiazepines (rats: 1-50 mg/kg, intraperitoneally; humans: 0.01-20.0mg/kg, with the most preferable range being 1-10 mg/kg body weight perday orally).

The invention illustratively disclosed herein suitably may explicitly bepracticed in the absence of any element which is not specificallydisclosed herein. While various embodiments of the present inventionhave been described in detail, it is apparent that various modificationsand alterations of those embodiments will occur to and be readilyapparent those skilled in the art. However, it is to be expresslyunderstood that such modifications and alterations are within the scopeand spirit of the present invention, as set forth in the appendedclaims. Further, the invention(s) described herein is capable of otherembodiments and of being practiced or of being carried out in variousother related ways. In addition, it is to be understood that thephraseology and terminology used herein is for the purpose ofdescription and should not be regarded as limiting. The use of“including,” “comprising,” or “having” and variations thereof herein ismeant to encompass the items listed thereafter and equivalents thereofas well as additional items while only the terms “consisting of” and“consisting only of” are to be construed in the limitative sense.

1-20. (canceled)
 21. A method of treating a condition of in a humanpatient comprising: pharmacologically activating a translocator proteinof 18 kDa (TSPO) by administering a therapeutically effective amount ofa pharmaceutical composition to the patient; wherein the condition isone of a chronic methamphetamine addiction; a medical consequence ofmethamphetamine use; a behavioral consequence of methamphetamine use;and a neuroinflammatory response.
 22. The method of claim 21 wherein thecondition is chronic methamphetamine addiction.
 23. The method of claim21 wherein the condition is a medical consequence of methamphetamineuse.
 24. The method of claim 23 wherein the medical consequence iscognitive defect.
 25. The method of claim 21 wherein the condition is abehavioral consequence of methamphetamine use.
 26. The method of claim25 wherein the behavioral consequence is one of increased violence,risk-taking behaviors, propensity for criminal activity, and aberrantsexual behavior.
 27. The method of claim 21 wherein the condition is aneuroinflammatory response.
 28. The method of claim 21 wherein the humanis a female.
 29. The method of claim 21 wherein the pharmaceuticalcomposition includes a benzodiazepine that targets TSPO over a GABAAreceptor.
 30. The method of claim 29 further comprising administering atherapeutically effective amount of one or more of an agonist(activator) of potassium-chloride co-transporter 2 (KCC2) and aninhibitor (antagonist) of 20 alpha-hydroxysteroid dehydrogenase (20alpha-HSD) and therapeutically acceptable salt, solvate, clathrate,stereoisomer, enantiomer or prodrug of these compounds or mixturesthereof.
 31. The method of claim 21 wherein the pharmaceuticalcomposition includes a benzodiazepine that has a halogen bound to a 4′carbon in the benzodiazepine.
 32. The method of claim 21 wherein thepharmaceutical composition includes one or more peripheralbenzodiazepine receptor ligands selected from a group consisting of:Ro5-5115, Ro5-5119, Ro5-5120, Ro5-5122, Ro5-5888, Ro5-4864, Ro5-6524,Ro5-6528, Ro5-6531, Ro5-6900, Ro5-6902, Ro5-6945, and Ro5-6993, oxazepamand therapeutically acceptable salt, solvate, clathrate, stereoisomer,enantiomer or prodrug of these compounds or mixtures thereof.
 33. Themethod of claim 32 wherein the peripheral benzodiazepine receptorligands is one of Ro5-4864, oxazepam and therapeutically acceptablesalt, solvate, clathrate, stereoisomer, enantiomer or prodrug of thesecompounds or mixtures thereof.
 34. A therapeutic product comprising: afirst component being a benzodiazepine with a halogen moiety in a 4′position or a therapeutically acceptable salt, solvate, clathrate,stereoisomer, enantiomer or prodrug of thereof, and a second componentbeing one of an agonist (activator) of potassium-chloride co-transporter2 (KCC2) and an inhibitor (antagonist) of 20 alpha-hydroxysteroiddehydrogenase (20 alpha-HSD) or a therapeutically acceptable salt,solvate, clathrate, stereoisomer, enantiomer or prodrug of thesecompound or mixtures thereof.
 35. The therapeutic product of claim 34wherein the second component is an agonist (activator) ofpotassium-chloride co-transporter 2 (KCC2) or a therapeuticallyacceptable salt, solvate, clathrate, stereoisomer, enantiomer or prodrugof thereof.
 36. The therapeutic product of claim 34 wherein the secondcomponent is an inhibitor (antagonist) of 20 alpha-hydroxysteroiddehydrogenase (20 alpha-HSD) or a therapeutically acceptable salt,solvate, clathrate, stereoisomer, enantiomer or prodrug of thereof. 37.The therapeutic product of claim 34 wherein the second componentincludes both an agonist (activator) of potassium-chlorideco-transporter 2 (KCC2) or a therapeutically acceptable salt, solvate,clathrate, stereoisomer, enantiomer or prodrug of thereof, and aninhibitor (antagonist) of 20 alpha-hydroxysteroid dehydrogenase (20alpha-HSD) or a therapeutically acceptable salt, solvate, clathrate,stereoisomer, enantiomer or prodrug of thereof.
 38. The therapeuticproduct of claim 34 wherein the first component is selected from a groupconsisting of: Ro5-5115, Ro5-5119, Ro5-5120, Ro5-5122, Ro5-5888,Ro5-4864, Ro5-6524, Ro5-6528, Ro5-6531, Ro5-6900, Ro5-6902, Ro5-6945,and Ro5-6993, oxazepam and therapeutically acceptable salt, solvate,clathrate, stereoisomer, enantiomer or prodrug of these compounds ormixtures thereof.
 39. A therapeutic product comprising: a firstcomponent being one of Ro5-4864 and oxazepam or a therapeuticallyacceptable salt, solvate, clathrate, stereoisomer, enantiomer or prodrugor mixtures thereof, a second component being an agonist (activator) ofpotassium-chloride co-transporter 2 (KCC2) and therapeuticallyacceptable salt, solvate, clathrate, stereoisomer, enantiomer or prodrugmixture thereof; and a third component being an inhibitor (antagonist)of 20 alpha-hydroxysteroid dehydrogenase (20 alpha-HSD) or atherapeutically acceptable salt, solvate, clathrate, stereoisomer,enantiomer or prodrug or mixture thereof.